Download Having Children When You Have Pompe Disease

Having Children When You Have Pompe Disease
Pompe disease is a genetic
disease. Genetic diseases are
caused by abnormalities in
gene(s) or chromosomes. Genetic
diseases are passed from parents
to their children through genes.
Genes are basic units of heredity
and consist of small segments of
DNA that contain instructions for
processes and structures in the
human body, as well as features
that make a person unique. Some
genes control traits and features
such as gender, height, and eye
color. Other genes control bodily
processes, such as making the
enzymes that help the body
function.
Pompe disease is caused by a
genetic mutation that blocks the
production of an enzyme (a type of
protein)
called
acid
alphaglucosidase. This can lead to muscle damage throughout the body. You can only get
Pompe disease when you inherit, 1 copy of the defective gene from each parent, as
shown in this diagram. This is called autosomal recessive inheritance. For this reason,
men and women with a family history of Pompe disease may be concerned about
having children. Partners of people with Pompe disease may want to know if they are
carriers of the defective gene. Women who have Pompe disease may also worry about
the health risks of becoming pregnant. If you are thinking about having children, it is
important to be aware of both the chances of passing on the disease, and the problems
that could arise before, during, and after pregnancy. If you already have children, you
may want to know their risk for having the disease or passing it on. This handout talks
about some of the issues you will want to think about. It also describes the tests that
can help predict whether your baby will be affected by Pompe disease.
Q: What is human genetics and what does it have to do with Pompe disease?
A: Human genetic makeup is encoded into complex chemical structure called DNA
(short for deoxyribonucleic acid). DNA molecules form the basis of structures called
chromosomes. Every person has 46 chromosomes, grouped into 23 pairs, which are
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found inside cell’s nucleus. Each chromosome is itself divided into thousands of smaller
segments, called genes.
Among the 23 pairs of chromosomes, one pair, called sex chromosomes, determines a
person’s gender. The other 22 pairs, called autosomes, determine all other non-genderrelated traits.
Because genes are a part of chromosomes, they also come in pairs - during
reproduction, each parent passes on a copy of half of their genetic material to their
offspring.
Each gene pair works together to control a specific function or activity within the cell.
Some have relatively small significance, such as defining a person’s hair or eye color,
while others control important cellular activities, such as the production of vital enzymes
needed for healthy functioning.
A gene mutation is a permanent alteration in a gene. Disease results from the gene's
inability to produce a protein the body needs for normal functioning. The altered
diseases produced by gene mutations can be mild, severely debilitating, or fatal.
The gene that causes Pompe disease is called GAA and is located on chromosome 17,
which is an autosomal chromosome. (More on this under the section titled Genetic
Heterogeneity).
There are many different defects, or mutations, that can affect the GAA gene. Most
people with Pompe disease inherit two different GAA gene mutations, one from each of
their parents. Researchers have already identified approximately 300 distinct mutations
(although not every one of these always causes Pompe disease), and more continue to
be found.
For more detailed information about genetic heterogeneity go to the Pompe Center,
Erasmus MC Rotterdam website (http://www.pompecenter.nl/en/?Disease)
Q: What does it mean to be a carrier of Pompe disease?
A: The term "carrier" is used for any person who is symptom-free (or has only very mild
symptoms) despite having a medical condition. Carriers of Pompe disease have one
bad copy of the GAA gene. The one good copy of the GAA gene allows for the
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production of enough enzymes to keep cells functioning properly. A carrier’s enzyme
activity is usually somewhat lower than normal, but they usually do not experience any
symptoms.
Q: Does Pompe Disease affect one ethnic group more than others?
A: Research has shown that Pompe disease is pan-ethnic—it occurs in people of all
ethnicities and races. There does appear to be a slightly higher incidence rate in certain
groups:
•
In infants, the disease has a higher frequency among African-Americans and
people from southern China and Taiwan.
•
Among adults, the disease has a higher frequency in the Netherlands.
In addition, specific gene mutations have been found to be more common in certain
ethnic groups or nationalities. It’s still unclear exactly why these higher frequencies
exist in certain groups, although the disease’s genetic basis and family inheritance
patterns are likely major contributing factors.
Q: How do you inherit Pompe disease?
A: Pompe disease is a genetic disorder, passed down from parent to child in an
autosomal recessive manner. Autosomal recessive diseases are relatively rare,
because to get Pompe disease you must inherit one bad copy of the gene from both
parents, not from just from one parent. So that means both parents must have at least
one bad copy of the gene.
Read more at http://www.wrongdiagnosis.com/genetics/recessive.htm?ktrack=kcplink
Inheritance Scenarios:
• If one parent has Pompe disease and the other parent is unaffected:
o There is a 100% chance the child will be a carrier. The parent with Pompe
disease has two bad copies of the gene, so the child will always get one
bad copy of the gene from that parent, and one good copy of the gene
from the parent who is unaffected.
• If one parent has Pompe disease, and the other parent is a carrier:
o
There is a 50% chance the child will get Pompe disease. The child will get
one bad copy of the gene from the parent with Pompe disease, and a 50%
chance of getting a second bad copy of the gene from the parent who is a
carrier.
o
There is a 50% chance the child will be a carrier. The child will get one
bad copy of the gene from the parent with Pompe disease, and a 50%
chance of getting one good copy of the gene from the parent who is a
carrier.
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• If one parent is a carrier of Pompe disease and the other parent is unaffected:
o
There is no chance the child will get Pompe disease. The child will always
get one good copy of the gene from the parent who is unaffected and 50%
chance of getting a second good copy of the gene from the parent who is
a carrier.
o
There is a 50% chance the child will be a carrier. The child will always get
one good copy of the gene from the parent who is unaffected and 50%
chance of getting one bad copy of the gene from the parent who is a
carrier.
• If both parents are carriers, each child born to them has a:
25% chance of having the disease
o 50% chance of being a carrier of the disease
o 25% chance of neither having the disease nor being a carrier of the
disease
o
Q: Are there tests to determine if my partner and I are Pompe carriers?
A: The only way to know for sure if someone is a carrier of the genetic mutation that
causes Pompe disease is by doing DNA testing, or direct mutation analysis (also called
genotyping). This involves taking a sample of blood, separating the DNA from the cells,
and then looking for the specific mutations that are known to cause Pompe disease.
Molecular testing of DNA mutations is possible because more than 150 mutations of the
GAA gene have been identified in people with Pompe disease. Some of these
mutations are limited to particular ethnic groups.
Since Pompe disease is so rare and the risk for being a carrier is so small, carrier
testing is not done unless there is a family member with the disease whose mutations
are known. Mutation analysis is the only way to identify carriers, who do not have the
disease, but “carry” the gene defect and may pass it on to their own children - so it’s
particularly important to identify carriers within families with a history of the disease.
Q: If I should be pregnant now, is there a way to find out if my unborn child has
Pompe disease?
A: Yes, there are prenatal screening tests that can be done early in pregnancy to see if
your fetus (unborn child) is affected with Pompe disease.
Chorionic villus (tiny finger-shaped growths found in the placenta) sampling, or CVS, is
done between the 10th and 12th week of pregnancy. This test involves taking a small
sample of tissue from the growing placenta (an organ that connects the developing
fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange
via the mother's blood supply) and measuring enzyme activity.
Prenatal testing is also available by enzyme analysis in amniocytes (amniocyte is a cell
of a fetus which is suspended in the amniotic fluid) taken from the amniotic fluid
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(amniocentesis). An amniocentesis can be performed as early as the 12th week of
pregnancy and can provide results as quickly as a few days. This test checks for
enzyme activity and allows for DNA analysis by testing cells taken from fluid in the
womb.
DNA testing may also be done to compare the DNA from the fetus with the DNA of the
parents or an affected brother or sister.
The results of these prenatal tests can help guide choices about the pregnancy and
prepare for the baby’s arrival.
In summary, for prenatal diagnosis:
• Molecular testing is the preferred method when both mutations are known
•
Enzyme analysis in chorionic villus samples is preferred when molecular testing
is not feasible, or when enzyme analysis is an adjunct to molecular testing,
•
Confirmation in amniocytes (cell of a fetus which is suspended in the amniotic
fluid) may be considered if mutations are known.
Q. My healthcare provider has advised me to get genetic counseling before I get
pregnant. What is a Genetic Counselor?
A: Genetic counselors are health care professionals with unique specialized graduate
degrees and experience in the areas of both medical genetics and counseling. Genetic
counselors work as members of a health care team, providing risk assessment,
education and support to individuals and families at risk for, or diagnosed with, a variety
of inherited conditions, like Pompe disease. Genetic counselors also interpret genetic
testing, provide supportive counseling, and serve as patient advocates.
If you or a family member has Pompe disease, or a carrier for Pompe disease, genetic
counseling can help you understand your chances for having a baby with the disease.
Meeting with a genetic counselor before you get pregnant will help you sort out all the
issues that may affect your decision to have children:
A genetic counselor will be able to:
• Explain family inheritance patterns and identify potentially at-risk individuals.
• Provide balanced information about what genetic testing involves, in order to
support decisions about who to test
• Help family members cope with positive test results.
• Provide guidance on genetic issues such as family planning and prenatal testing.
If you are already pregnant the genetic counselor can talk to you about prenatal
testing for your unborn child. Should you choose to go ahead with genetic testing; the
genetic counselor will help you make appointments for the tests and provide the support
you need once you get the test results back. For example, if you find out your unborn
child is affected by Pompe disease, the genetic counselor can help you explore your
options and cope with the difficult choices ahead of you. Since the process of getting
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tested and waiting for results takes time, it is important to seek genetic counseling as
early as possible.
Q: Should I be treated with lumizyme if I become pregnant?
A: Animal-reproduction studies have not demonstrated a fetal risk but there are no
controlled studies in pregnant women at this time to confirm this. So Lumizyme should
only be used during pregnancy if clearly needed.
The Lumizyme Prescribing Information document states the following:
Teratogenic Effects (definition below): Pregnancy Category B. Reproduction studies
have been performed in pregnant mice at intravenous doses up to 40 mg/kg/day
(plasma AUC of 64.6 mg•min/mL, 0.4 times the human steady-state exposure at the
recommended bi-weekly dose) and in pregnant rabbits at intravenous doses up to 40
mg/kg/day (plasma AUC of 85 mg•min/mL, 0.5 times the human steady-state exposure
at the recommended bi-weekly dose) and have revealed no evidence of impaired fertility
or harm to the fetus due to alglucosidase alfa. There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction studies are not
always predictive of human response, Lumizyme should be used during pregnancy only
if clearly needed. Women of childbearing potential are encouraged to enroll in the
Pompe Registry
Teratology is the study of abnormalities of physiological development. It is often
thought of as the study of birth defects (congenital anomalies).
Labor and Delivery
Information on the effect of Myozyme/Lumizyme (USA) on labor and delivery is
unknown. Pregnant women are encouraged to enroll in the Pompe Registry.
Nursing Mothers
It is not known whether Myozyme/Lumizyme (USA) is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised when
Myozyme/Lumizyme (USA) is administered to a nursing woman. Nursing women are
encouraged to enroll in the Pompe Registry.
http://www.lumizyme.com/pdfs/lz_pi.pdf.
If you are interested in learning more about Pregnancy Categories, please refer to
Attachment 1.
Q: Can I get pregnant if I have Pompe disease?
A: Pompe disease does not appear to affect fertility (the ability to conceive a child).
Women diagnosed with Pompe disease also do not seem to have a higher risk for
miscarriage (loss of the pregnancy). However, if one partner has severe muscle
weakness, scoliosis (curvature of the spine), or contractures (muscle tightness), having
sexual intercourse may be difficult. If you are concerned about your risk for having a
child with Pompe disease because you and your partner are both carriers, you may
want to consider other options, such as adoption or conception with donor eggs or
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sperm. It is important to explore these choices with your healthcare provider and with a
genetic counselor so that you can make informed decisions.
Q: I have Pompe disease and I want to start a family. How will pregnancy affect
my health?
A: Although having Pompe disease should not affect your ability to get pregnant or
carry a pregnancy to term; there are some health concerns to be aware of, especially if
you are severely affected.
Weight gain: The biggest concern is the extra weight you will gain when you are
pregnant. If you already have a lot of muscle weakness, the weight you gain during your
pregnancy can cause lower back pain and make it harder to walk or keep your balance.
Scoliosis can make these problems worse. You may need to use a wheelchair as you
get further along in the pregnancy.
Breathing: Whether your muscle weakness is mild or severe, you may have more
trouble breathing as you gain weight. Be sure to tell your healthcare provider if you
notice these symptoms: shortness of breath, morning headaches, fatigue, dizziness,
confusion, or sleeping problems. Using a ventilator may help you breathe more easily.
Because of these concerns, you will need to be seen by both a healthcare provider who
treats high risk pregnancies and one who treats your Pompe disease. It is important to
have these doctors work together to manage your care.
Delivery: If muscle weakness or scoliosis is severe, your baby may need to be delivered
through the abdomen instead of the vagina. This is called a Cesarean section (Csection). If a C-section must be performed, it will be necessary to plan in advance for
the anesthesia you may need (see the handouts Common health concerns and
Breathing problems in Pompe disease).
Recovery: After the baby is born, it may take longer for you than for others to recover
and lose the extra weight you gained. It may also be hard to lift, carry, or nurse your
newborn. Be prepared to seek advice from other Pompe parents and your healthcare
team, and to get help at home if you need it.
Where to Learn More:
These groups can help you find answers to any other questions you may have about
pregnancy or family planning issues related to Pompe disease.
•
International Pompe Association (IPA) is a global federation of Pompe disease
patient groups. The IPA helps patients, family members, and healthcare
providers from around the world share their experiences and knowledge across
continents and cultures. To find the contact for your country, visit the IPA Web
site at www.worldpompe.org
•
Muscular Dystrophy Association (MDA): The MDA offers fact sheets on
genetic testing, inheritance patterns, and pregnancy for people affected by
neuromuscular diseases.
Visit www.muscular-dystrophy.org and click on
“Information and Resources”
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•
National Society of Genetic Counselors (NSGC) has an online directory of
genetic counselors in the United States and around the world. To search the
listings, visit www.nsgc.org and click on “Find a Counselor”. http://www.nsgc.org
•
The Pompe Center at Erasmus Medical Center in the Netherlands maintains
the most up-to-date record of mutations that have been identified for the GAA
gene. To learn about advances in research, treatment, and genetic testing for
Pompe disease, visit the Pompe Center Web site at www.pompecenter.nl
•
American College of Medical Genetics (ACMG) Practical Guidelines:
Pompe Disease Diagnosis and Management Guideline 2006. Vol. 8. No. 5. The
ACMG guidelines were designed as an educational resource for physicians and
other health care providers.
•
The Genzyme Corporation’s Pompe Community website www.pompe.com:
offers the Pompe community comprehensive information on the disease, as well
as resources and support to help manage the challenges it may bring.
•
Pompe Pregnancy Sub-Registry (Observational Study): The objective of this
study is to track pregnancy outcomes in women with Pompe Disease and to
follow infants born to women with Pompe Disease. http://www.clinicaltrials.gov/
•
Pompe Lactation Sub-Registry (Observational Study): The objective of this
study is to determine if alglucosidase alfa is present in breast milk from mothers
with Pompe Disease being treated with Myozyme® and to measure breast milk
production and composition in women with Pompe Disease who receive
Myozyme®. http://www.clinicaltrials.gov/
•
Know Your Genes: A Genetic Disease Foundation
www.knowyourgenes.org/genes101.shtml
•
The Global Genes Project™ exists to unify, support, build awareness and raise
much needed funds for those affected by rare disease. The Global Genes
Project™ campaign will broadly promote the needs of the rare disease
community as a whole, engaging the general public, garnering corporate support
under the unifying symbol of hope ~ the blue denim ribbon.
www.globalgenesproject.org
o The following videos have been developed by some of the Global Genes
Project rare disease partners to you help you better understand Genetics:
ƒ Genetics 101 Part 1: What are genes? Produced by 23andMe
ƒ Genetics 101 Part 2: What are SNPs? Produced by 23andMe
ƒ Genetics 101 Part 3: Where do your genes come from? Produced
by 23andMe
ƒ Genetics 101 Part 4: What is phenotype? Produced by 23andMe
ƒ What Genes Means! Produced by JeansforGenes
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References:
• ACMG Practical Guidelines: Pompe Disease Diagnosis and Management
Guideline 2006. Vol. 8. No. 5
• www.pompe.com
• http://en.wikipedia.org/wiki/Pregnancy_category
• http://www.tga.gov.au/docs/html/medpreg.htm
• http://www.safefetus.com/fda_category.asp
• http://www.wrongdiagnosis.com/genetics/index.htm
• http://www.pompecenter.nl/en/?Disease
This publication is designed to provide general information in regard to the subject
matter covered. It is distributed as a public service by the International Pompe
Association, with the understanding that the International Pompe Association is not
engaged in rendering medical or other professional services. Medicine is a constantly
changing science. Human error and changes in practice make it impossible to certify the
precise accuracy of such complex materials. Confirmation of this information from other
sources, especially one’s physician, is required.
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ATTACHMENT 1: Pregnancy Categories
Pregnancy Categories:
The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal
injury due to the pharmaceutical, if it is used as directed by the mother during
pregnancy. It does not include any risks conferred by pharmaceutical agents or their
metabolites that are present in breast milk.
Every drug has specific information listed in its product literature. In the UK, while no
preset categories are applied, the British National Formulary gives a table of drugs to be
avoided or used with caution in pregnancy, and does so using a limited number of key
phrases.
In 1979, the United States Food and Drug Administration (FDA) introduced a
classification of fetal risks due to pharmaceuticals. This was based on a similar system
that was introduced in Sweden one year earlier.
United States FDA Pharmaceutical Pregnancy Categories
Pregnancy Category A: Adequate and well-controlled human studies have failed to
demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no
evidence of risk in later trimesters).
Pregnancy Category B: Animal reproduction studies have failed to demonstrate a risk
to the fetus and there are no adequate and well-controlled studies in pregnant women
OR Animal studies have shown an adverse effect, but adequate and well-controlled
studies in pregnant women have failed to demonstrate a risk to the fetus in any
trimester.
Pregnancy Category C: Animal reproduction studies have shown an adverse effect on
the fetus and there are no adequate and well-controlled studies in humans, but potential
benefits may warrant use of the drug in pregnant women despite potential risks.
Pregnancy Category D: There is positive evidence of human fetal risk based on
adverse reaction data from investigational or marketing experience or studies in
humans, but potential benefits may warrant use of the drug in pregnant women despite
potential risks.
Pregnancy Category X: Studies in animals or humans have demonstrated fetal
abnormalities and/or there is positive evidence of human fetal risk based on adverse
reaction data from investigational or marketing experience, and the risks involved in use
of the drug in pregnant women clearly outweigh potential benefits.
One characteristic of the FDA definitions of the pregnancy categories is that the FDA
requires a relatively large amount of high-quality data on a pharmaceutical for it to be
defined as Pregnancy Category A. As a result of this, many drugs that would be
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considered Pregnancy Category A in other countries are allocated to Category C by the
FDA. 1
References:
http://www.safefetus.com/fda_category.asp
http://en.wikipedia.org/wiki/Pregnancy_category
Australia’s Pregnancy Categories
Australia has a slightly different pregnancy category system from the United States notably the subdivision of Category B. The system, as outlined below, was established
by the Congenital Abnormalities Sub-committee of the Australian Drug Evaluation
Committee (ADEC).
Pregnancy Category A: Drugs which have been taken by a large number of pregnant
women and women of childbearing age without an increase in the frequency of
malformations or other direct or indirect harmful effects on the fetus having been
observed.
Pregnancy Category B1: Drugs which have been taken by only a limited number of
pregnant women and women of childbearing age, without an increase in the frequency
of malformation or other direct or indirect harmful effects on the human fetus having
been observed. Studies in animals have not shown evidence of an increased
occurrence of fetal damage.
Pregnancy Category B2: Drugs which have been taken by only a limited number of
pregnant women and women of childbearing age, without an increase in the frequency
of malformation or other direct or indirect harmful effects on the human fetus having
been observed. Studies in animals are inadequate or may be lacking, but available
data show no evidence of an increased occurrence of fetal damage.
Pregnancy Category B3: Drugs which have been taken by only a limited number of
pregnant women and women of childbearing age, without an increase in the frequency
of malformation or other direct or indirect harmful effects on the human fetus having
been observed. Studies in animals have shown evidence of an increased occurrence of
fetal damage, the significance of which is considered uncertain in humans.
Pregnancy Category C: Drugs which, owing to their pharmaceutical effects, have
caused or may be suspected of causing, harmful effects on the human fetus or neonate
without causing malformations. These effects may be reversible.
Pregnancy Category D: Drugs which have caused are suspected to have caused or
may be expected to cause, an increased incidence of human fetal malformations or
irreversible damage. These drugs may also have adverse pharmacological effects.
Pregnancy Category X: Drugs that have such a high risk of causing permanent damage
to the fetus that they should NOT be used in pregnancy or when there is a possibility of
pregnancy.
1
http://www.safefetus.com/fda_category.asp; http://en.wikipedia.org/wiki/Pregnancy_category
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The sub-categories of Category B, while offering additional information which may be of
benefit in evaluating the risk vs benefit, presents its own problem of data reliability since human data is lacking or inadequate, the subcategories are based on animal data.
Furthermore, allocation of a drug in Category B does not necessarily imply greater
safety than Category C.
Drugs in Category D are not absolutely contraindicated in pregnancy, unlike Category
X. In some cases Category D was assigned to a drug on the basis of suspicion. 2
http://www.tga.gov.au/hp/medicines-pregnancy-categorisation.htm
Germany’s Pregnancy Categories
Gr 1: Extensive human testing and animal studies have not shown that the drug is
embryotoxic / teratogenic.
Gr 2: Extensive human testing of the drug have not shown that the drug is embryotoxic
/ teratogenic.
Gr 3: Extensive human testing of the drug has not shown that the drug is embryotoxic /
teratogenic. However, the drug appears to be embryotoxic / teratogenic in animals.
Gr 4: There have been no adequate and well-controlled studies of the drug's effects on
humans available. Animal studies have shown no embryotoxic/teratogenic effects.
Gr 5: There have been no adequate and well-controlled studies of the drug's effects on
humans available.
Gr 6: There have been no adequate and well-controlled studies of the drug's effects on
humans on pregnant women. Animal studies have shown embryotoxic/teratogenic
effects.
Gr 7: There is a risk that the drug is embryotoxic / teratogenic to the human fetus, at
least in the first trimester.
Gr 8: There is a risk that the drug is toxic to fetuses throughout the second and third
trimester.
Gr 9: There is a risk that the drug causes prenatal complications or abnormalities.
Gr 10: There is a risk that the drug causes hormone specific action on the human fetus.
Gr 11: There is a known risk that the drug is a mutagen/carcinogen. 3
http://en.wikipedia.org/wiki/Pregnancy_category
2
3
http://www.tga.gov.au/docs/html/medpreg.htm
http://en.wikipedia.org/wiki/Pregnancy_category
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